According to estimates from the Centers for Disease Control and Prevention (CDC), about 30% of the United States population is obese and 65% is overweight. One of the major consequences of these high rates is manifested by the increased prevalence of type 2 diabetes mellitus (T2D), a disorder that is characterized by high blood glucose in the context of insulin resistance that progresses towards pancreatic β-cell dysfunction leading to insulin deficiency [1]. There are an estimated 23.6 million people in the U.S. (7.8% of the population) with diabetes, 90% of whom are type 2 diabetics [2]. With prevalence rates doubling between 1990 and 2005, CDC has characterized this increase as an epidemic. In parallel with the obesity and diabetes pandemics, the rates of inflammatory diseases are also growing dramatically worldwide and current anti-inflammatory medications such as nonsteroidal anti-inflammatory drugs (NSAID) have adverse side effects. In light of the rapidly growing need for diabetes and anti-inflammatory products, the industry is now faced with the challenge of finding safe and effective compounds for managing blood glucose levels in diabetic patients and treating chronic inflammatory and infectious diseases.
Current antidiabetic drugs used in the management of T2D elicit important insulin-sensitizing and anti-inflammatory effects. However, side effects associated with using these medications are serious, any of which may limit their use [3]. For example, sulfonylureas, the first widely used oral hypoglycemic medications, cause hypoglycemia [4]; Biguanides are typically reserved for patients experiencing gastrointestinal side effects [5] and TZDs could lead to an increase in the incidence of liver damage and potential liver failure, fluid retention, weight gain and congestive heart failure [6]. Thus, it is critical to discover novel, naturally occurring drugs and nutraceuticals against T2D. A study linked the TZD drug Avandia (GlaxoSmithKline) to a 43 percent increased risk of heart attack. In September of 2010 the U.S. Food and Drug Administration (FDA) significantly restricted the use of Avandia. The European Medicines Agency pulled Avandia off the European market in 2010.
In similar action, current therapies against autoimmune and inflammatory diseases such as NSAID have significant side effects, including immune suppression, which can lead to increase risk of cancer and infections. Thus, there is an urgent need to develop novel therapeutic and prophylactic agents that are more efficacious and safer.
Our team has developed computational and experimental approaches to effectively screen and discover novel classes of compounds for the prevention and treatment diabetes, cardiovascular disease, gut inflammation and inflammation-driven cancer that activate nuclear receptors through a novel mechanism of action. Of note is the discovery of a peroxisome proliferator-activated receptor (PPAR) γ-activating and anti-inflammatory phytohormone, ABA, which is also a potent insulin-sensitizer. PPAR γ is one of three PPAR isoforms (α, δ, and γ) that is a component of an extensive group of transcription factors controlling adipogenesis and glucose homeostasis, and both of these processes directly affect obesity and T2D [7]. ABA is a phytochemical regulating fundamental physiological functions in plants but it can also be endogenously synthesized in mammalian cells, including granulocytes, pancreatic β-cells and monocytes [8].
PPAR γ is required for ABA to induce its full spectrum of effects [9], but our unpublished data indicate that ABA does not bind directly to the ligand-binding domain (LBD) of PPAR γ. Therefore, the complete mechanism of activation of PPAR γ by ABA is unknown. Recently, Sturla and his colleagues provided in vitro results suggesting that the lanthionine synthetase component C-like protein 2 (LANCL2) may mediate ABA signaling in human granulocytes [10]. LANCL2 is a member of the eukaryotic LANCL protein family, which is related to the bacterial lanthionine synthetase component C [11]. We posit that LANCL2 is a target for drugs and nutraceuticals that can be used in the prevention and treatment of diabetes and inflammatory diseases [12].